Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2

Nhi Hin, Morgan Newman, Jan Kaslin, Alon M. Douek, Amanda Lumsden, Seyed Hani Moussavi Nik, Yang Dong, Xin Fu Zhou, Noralyn B. Manucat-Tan, Alastair Ludington, David L. Adelson, Stephen Pederson, Michael Lardelli

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Abstract

Background The molecular changes involved in Alzheimer's disease (AD) progression remain unclear since we cannot easily access antemortem human brains. Some non-mammalian vertebrates such as the zebrafish preserve AD-relevant transcript isoforms of the PRESENILIN genes lost from mice and rats. One example is PS2V, the alternative transcript isoform of the PSEN2 gene. PS2V is induced by hypoxia/oxidative stress and shows increased expression in late onset, sporadic AD brains. A unique, early onset familial AD mutation of PSEN2, K115fs, mimics the PS2V coding sequence suggesting that forced, early expression of PS2V-like isoforms may contribute to AD pathogenesis. Here we use zebrafish to model the K115fs mutation to investigate the effects of forced PS2V-like expression on the transcriptomes of young adult and aged adult brains. Methods We edited the zebrafish genome to model the K115fs mutation. To explore its effects at the molecular level, we analysed the brain transcriptome and proteome of young (6-month-old) and aged (24-month-old) wild type and heterozygous mutant female sibling zebrafish. Finally, we used gene co-expression network analysis (WGCNA) to compare molecular changes in the brains of these fish to human AD. Results Young heterozygous mutant fish show transcriptional changes suggesting accelerated brain aging and increased glucocorticoid signalling. These early changes precede a transcriptional 'inversion' that leads to glucocorticoid resistance and other likely pathological changes in aged heterozygous mutant fish. Notably, microglia-associated immune responses regulated by the ETS transcription factor family are altered in both our zebrafish mutant model and in human AD. The molecular changes we observe in aged heterozygous mutant fish occur without obvious histopathology and possibly in the absence of Aâ. Conclusions Our results suggest that forced expression of a PS2V-like isoform contributes to immune and stress responses favouring AD pathogenesis. This highlights the value of our zebrafish genetic model for exploring molecular mechanisms involved in AD pathogenesis.

Original languageEnglish
Article numbere0227258
Number of pages36
JournalPLoS One
Volume15
Issue number1
DOIs
Publication statusPublished - 24 Jan 2020

Bibliographical note

This is an open access article distributed under the terms of the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.

Keywords

  • brain aging
  • K115fs mutation
  • PSEN2 gene
  • Alzheimer's disease
  • zebrafish genome
  • zebrafish model

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    Hin, N., Newman, M., Kaslin, J., Douek, A. M., Lumsden, A., Nik, S. H. M., Dong, Y., Zhou, X. F., Manucat-Tan, N. B., Ludington, A., Adelson, D. L., Pederson, S., & Lardelli, M. (2020). Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2. PLoS One, 15(1), [e0227258]. https://doi.org/10.1371/journal.pone.0227258